Biology subjects

Qvist, P.

Publications and source records attributed to Qvist, P..

9 recordsLinked to original sources

bioRxiv2025

BRD1 haploinsufficiency alters early neuronal programming and disrupts maturation in human induced glutamatergic neurons

BRD1 is an epigenetic regulator implicated in neurodevelopmental and psychiatric disorders, yet its role in human neuronal differentiation, maturation, and function remains poorly understood. Here we show that BRD1 haploinsufficiency disrupts early neuronal programming, resulting in accelerated maturation and altered neurodevelopmental trajectories in human induced glutamatergic neurons. Transcriptomic profiling reveals an early shift toward neuronal identity, characterized by downregulation of pluripotency markers and persistent upregulation of genes involved in synapse assembly and organization, including GRIA3. Despite this, BRD1+/- neurons form significantly smaller synapses and display increased neuronal activity. Our findings highlight BRD1 as a key regulator of neurodevelopmental timing and synaptic maturation, and network activity reinforcing growing evidence that disruptions in chromatin-mediated control of differentiation and synaptic organization contribute to neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

Porcine model of BRD1 haploinsufficiency reveals neurodevelopmental, behavioral, and molecular altera-tions relevant to psychiatric disorders

Psychiatric disorders are complex conditions characterized by substantial overlap in genetic risk and shared biological mechanisms. However, how individual risk genes contribute to shared disease mechanisms and disorder-specific phenotypes remains poorly understood. BRD1 has emerged as a chromatin-associated regulator with transdiagnostic relevance across psychiatric disorders and a central role in gene regulatory networks enriched for psychiatric risk genes. To investigate the biological consequences of reduced BRD1 function in a translationally relevant system, we generated a minipig model harboring a monoallelic deletion in BRD1 and performed longitudinal neuroimaging together with behavioral and multi-omics profiling. BRD1 haploinsufficient minipigs displayed normal growth and exploratory behavior but exhibited subtle age-dependent differences in motivational behavior. Despite the absence of overt developmental abnormalities, longitudinal neuroimaging revealed genotype-associated structural differences primarily involving the cerebral cortex and caudate nucleus, suggestive of altered neurodevelopmental trajectories. Integrated multi-omics analyses revealed striking convergence across transcriptomic and metabolomic datasets, identifying coordinated perturbations of mitochondrial function, redox regulation, and phospholipid metabolism across multiple brain regions. Notably, these molecular alterations were not restricted to the central nervous system, as peripheral multi-omics profiling revealed systemic metabolic alterations, including altered phospholipid composition and glucose metabolism. Together, these findings indicate that BRD1 haploinsufficiency is associated with coordinated neurodevelopmental and metabolic alterations across brain and peripheral tissues. More broadly, this study provides systems-level insight into how a psychiatric risk gene influences interconnected neurodevelopmental and metabolic processes across multiple levels of biological organization and highlights the value of large-animal multi-omics models for translational neuropsychiatric research.

genetics↗

bioRxiv2024

A triple serine motif in the intracellular domains of sortilin-related receptors SorCS1-3 regulates neurotrophic activity

The Vps10p-domain receptors SorCS1-3 have been repeatedly associated with the development of neurological and psychiatric disorders. They have emerged as key regulators of synaptic activity and neurotrophic signaling, but the underlying molecular mechanism remains poorly understood. Here we report that the SorCS1-3 intracellular domains (ICDs) contain a conserved triple serine motif that potentially functions as a signaling switch to induce neurotrophic signaling in hippocampal neurons. We demonstrate that phosphorylation mimicking mutations of the SorCS1-3 triple serine motifs display neurotrophic activity independently of both their extracellular domains (ECDs) and BDNF, and that the substitution of serines to alanines renders neurons less responsive to BDNF. Hence, we develop triple serine motif-based cell-penetrating peptides that modulate downstream signaling kinases of the BDNF pathway, ultimately activating the transcription factor CREB. Taken together, we provide the first mechanistic insights into SorCS1-3 mediated neurotrophic signaling and use this knowledge to develop pharmacologically active modulators.

neuroscience↗

bioRxiv2024

APP and its intracellular domain modulate Alzheimers disease risk gene networks in transgenic APPsw and PSEN1M146I porcine models

Alzheimers disease (AD) is a progressive neurodegenerative disorder and the most frequent cause of dementia. The disease has a substantial genetic component comprising both highly penetrant familial mutations (APP, PSEN1, and PSEN2) and sporadic cases with complex genetic etiology. Mutations in APP and PSEN1/2 alter the proteolytic processing of APP to its metabolites, including A{beta} and APP Intracellular Domain (AICD). In this study, we use transgenic porcine models carrying the human APPsw and PSEN1M146I transgenes to demonstrate the pathobiological relevance of transcriptional regulation facilitated by APP and its AICD domain. Through molecular characterization of hippocampal tissue, we describe the differential expression of gene sets that cluster in molecular pathways with translational relevance to AD. We further identify phosphorylated and unphosphorylated AICD in differential complexes with proteins implicated in signal transduction and transcriptional regulation. Integrative genomic analysis of transcriptional changes in somatic cell cultures derived from pigs treated with {gamma}-secretase inhibitor demonstrates the importance of {gamma}-secretase APP processing in transcriptional regulation. Our data supports a model in which APP and, in particular, its AICD domain, modulates gene networks associated with AD pathobiology through interaction with signaling proteins. One Sentence SummaryUtilizing transgenic porcine models, our study reveals that Alzheimers disease-related mutations affect neuronal gene expression and highlights the role of the AICD domain of APP in modulating gene networks associated with Alzheimers pathobiology.

cell biology↗

bioRxiv2023

Sorting receptor SORCS2 facilitates a protective stress response in pancreatic islets

ObjectiveSORCS2 is an intracellular sorting receptor genetically associated with body mass index (BMI) in humans, yet its mode of action remains unknown. Elucidating the receptor function that defines its role in metabolic health is the objective of this work. MethodsCombining in vivo metabolic studies in SORCS2-deficient mouse models with ex vivo structural and functional analyses as well as single-cell transcriptomics of murine pancreatic tissues, we studied the pathophysiological consequences of receptor dysfunction for metabolism. ResultsOur studies identified an important role for SORCS2 in islet stress response essential to sustain glucose-stimulated insulin release. In detail, we show that SORCS2 is predominantly expressed in islet alpha cells. Loss of receptor expression coincides with the inability of these cells to produce osteopontin, a secreted factor that facilitates insulin release from beta cells under stress. In line with diminished osteopontin levels, beta cells in SORCS2- deficient islets show changes in gene expression patterns related to aggravated ER stress, protein misfolding, as well as mitochondrial dysfunction; and they exhibit defects in insulin granule maturation and a blunted response to glucose stimulation in vivo and ex vivo. Impaired glucose tolerance in receptor mutant mice coincides with alterations in body weight and composition. ConclusionOur data identified a novel concept in protective islet stress response involving the alpha cell receptor SORCS2 and provide experimental support for association of SORCS2 with metabolic control in humans.

molecular biology↗

bioRxiv2023

SorCS2 binds progranulin and regulates motor axon outgrowth

Motor neuron development requires an orchestrated action of trophic factors and guidance cues for axons to reach their targets. Here, we identify SorCS2 as a novel receptor for progranulin (PGRN) that is required for motor axon outgrowth in zebrafish and mice. In both species motor neurons express SorCS2, and PGRN is produced in cells juxta-positioned the projecting axon, but in mice the neurons also co-express PGRN. In zebrafish, sorcs2 knockdown produces stunted and aberrantly branched motor axons, and in Sorcs2-/- mice, forelimb innervation and motor neuron regeneration are substantially perturbed; phenotypes also observed in fish and mice lacking PGRN. SorCS2 binds PGRN and while motor neuron cultures from wildtype mice respond to exogenous PGRN by axon outgrowth, knockout neurons are unresponsive. Remarkably, when co-expressed in the same cells, SorCS2 controls secretion of PGRN. We conclude that SorCS2 navigates motor neuron development and enables axon regeneration through binding of PGRN.

developmental biology↗

bioRxiv2021

Enhanced Production of Mesencephalic Dopaminergic Neurons from Lineage-Restricted Human Undifferentiated Stem Cells

The differentiation of human pluripotent stem cells (hPSCs) into mesencephalic dopaminergic (mesDA) neurons requires a precise combination of extrinsic factors that recapitulates the in vivo environment and timing. Current methods are capable of generating authentic mesDA neurons after long-term culture in vitro; however, when mesDA progenitors are transplanted in vivo, the resulting mesDA neurons are only minor components of the graft. This low yield hampers the broad use of these cells in the clinic. In this study, we genetically modified pluripotent stem cells to generate a novel type of stem cells called lineage-restricted undifferentiated stem cells (LR-USCs), which robustly generate mesDA neurons. LR-USCs are prevented from differentiating into a broad range of nondopaminergic cell types by knocking out genes that are critical for the specification of cells of alternate lineages. Specifically, we target transcription factors involved in the production of spinal cord and posterior hindbrain cell types. When LR-USCs are differentiated under caudalizing condition, which normally give rise to hindbrain cell types, a large proportion adopt a midbrain identity and develop into authentic mesDA neurons. We show that the mesDA neurons are electrophysiologically active, and due to their higher purity, are capable of restoring motor behavior eight weeks after transplantation into 6-hydroxydopamine (6-OHDA)-lesioned rats. This novel strategy improves the reliability and scalability of mesDA neuron generation for clinical use.

neuroscience↗

bioRxiv2018

The behavioral and neurobiological effects of reduced Brd1 expression in mice are sex-biased and implicate gender dependent dysregulation of nuclear receptor mediated signaling in mental disorders

The schizophrenia and bipolar disorder associated gene, BRD1, encodes a scaffold protein that in complex with epigenetic modifiers regulate gene sets enriched for psychiatric disorder risk. Preclinical evidence from male Brd1+/- mice has previously implicated BRD1 with phenotypes of translational relevance to schizophrenia. Here we describe the phenotype of female Brd1+/- mice and report attenuated dendritic architecture and monoaminergic dysregulation accompanied by sex-specific changes in affective behaviors. In accordance, global gene expression profiling reveals regional dysregulation of gene sets enriched with major depressive disorder and schizophrenia risk in female and male Brd1+/- mice, respectively. Independent of sex, however, differentially expressed genes cluster in common functional pathways associated with psychiatric disorders, including mitochondrial dysfunction and oxidative phosphorylation as well as G-protein coupled-, and nuclear receptor mediated signaling. Accordingly, we provide in vitro evidence that BRD1 modulates the transcriptional drive of a subset of nuclear receptors (e.g. the vitamin D and glucocorticoid receptors). Moreover, we demonstrate enrichment of psychiatric disorder risk in the target genes of nuclear receptors, sex-biased expression of several nuclear receptor genes in the adult brain of Brd1+/- mice, and that sex-biased genes in general are enriched with nuclear receptor genes particularly at the earliest developmental stage of the human brain. Overall, our data suggests that the spatio-temporal interaction between BRD1 and subsets of nuclear receptors in the brain is sex-biased and that hampered BRD1 mediated regulation of target genes governed by certain nuclear receptors may significantly contribute to sex differences in psychopathology.

neuroscience↗

bioRxiv2017

Genome-wide association study implicates CHRNA2 in cannabis use disorder

Introductory paragraphCannabis is the most frequently used illicit psychoactive substance worldwide1. Life time use has been reported among 35-40% of adults in Denmark2 and the United States3. Cannabis use is increasing in the population4-6 and among users around 9% become dependent7. The genetic risk component is high with heritability estimates of 518-70%9. Here we report the first genome-wide significant risk locus for cannabis use disorder (CUD, P=9.31x10-12) that replicates in an independent population (Preplication=3.27x10-3, Pmetaanalysis=9.09x10-12). The finding is based on a genome-wide association study (GWAS) of 2,387 cases and 48,985 controls followed by replication in 5,501 cases and 301,041 controls. The index SNP (rs56372821) is a strong eQTL for CHRNA2 and analyses of the genetic regulated gene expressions identified significant association of CHRNA2 expression in cerebellum with CUD. This indicates a potential therapeutic use in CUD of compounds with agonistic effect on the neuronal acetylcholine receptor alpha-2 subunit encoded by CHRNA2. At the polygenic level analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance.

genomics↗